Process for alleviating pain

ABSTRACT

This invention relates to 2-(2-methylanilino)-nicotinic acid, the non-toxic pharmaceutically acceptable salts thereof and to the methods for the preparation and use thereof. The tangible embodiments of this invention are prepared by condensing a 2-halonicotinic acid, or a functionally reactive equivalent thereof, with an o-toluidine, or a functionally reactive equivalent thereof, to produce either 2-(2methylanilino)-nicotinic acid or a derivative which is convertible thereinto.

United States Patent 1 Aug. 22, 1972 Sherlock [54] PROCESS FORALLEVIATING PAIN [72] Inventor: Margaret H. Sherlock, 34 Parkway W.,Bloomfield, NJ. 07003 [73] Assignee: Schering Corporation, Bloomfield,

[22] Filed: Sept. 18, 1970 [21] Appl. No.: 73,659

Related US. Application Data [60] Division of Set. No. 866,012, Oct. 13,1969, abandoned, which is a continuation-in-part of Ser. No. 835,743,June 23, 1969, abandoned.

Primary Examiner.lerome D. Goldberg Attorney-Stephen B. Coan and RaymondA. Mc- Donald [57] ABSTRACT This invention relates to2-(2-methylanilino)-nicotinic acid, the non-toxic pharmaceuticallyacceptable salts thereof and to the methods for the preparation and usethereof. I

The tangible embodiments of this invention are prepared by condensing a2-ha1onicotinic acid, or a functionally reactive equivalent thereof,with an otoluidine, or a functionally reactive equivalent thereof, toproduce either 2-(2-methylanilino)-nicotinic acid or a derivative whichis convertible thereinto.

3 Claims, No Drawings PROCESS FOR ALLEVIATING PAIN This application is adivisional application of my application Ser. No. 866,012, filed Oct.13, 1969, now abandoned, which in turn was a continuation-in-part of myapplication Ser. No. 835,743, filed June 23, 1969, now abandoned.

The invention sought to be patented in one of its composition of matteraspects is described as residing in the concept of having the molecularstructure of 2- (2-methylanilino)-nicotinic acid, including the nontoxicpharmaceutically acceptable salts thereof.

The invention sought to be patented in another of its composition ofmatter aspects resides in the concept of pharmaceutical dosage formscontaining a novel compound of this invention.

The invention sought to be patented in one of its process aspects isdescribed as residing in the concept of producing analgesia upon theadministration of a therapeutically effective quantity of the novelcompounds of this invention.

In another of its process aspects, the invention sought to be patentedresides in the concept of condensing a 2halo-nicotinic acid or afunctionally reactive equivalent thereof with an o-toluidine or afunctionally reactive equivalent thereof to produce either 2-(2-methylanilino)-nicotinic acid or a derivative which is .convertiblethereinto.

The compounds are preferably prepared by heating together a 2-halo(preferably chloro or bromo) nicotinic acid with an o-toluidine, saidheating taking place in either a high boiling solvent such as xylene orcymene, or by merely melting the reactants in the presence of eachother. In the melt procedure, the reaction temperature will rise as thereaction proceeds. The reaction is completed generally after -30 minutesand is evidenced by a fall in the reaction temperature. The fused meltis then treated with a dilute aqueous base, such as for example, sodiumcarbonate or sodium hydroxide, and is extracted with a water immisciblesolvent. The product, in the form of the soluble salt, is in the aqueouslayer and is precipitated therefrom by acidifying with a dilute mineralacid and it is then filtered.

Alternatively, a lower alkyl ester of the 2-halonicotinic acid may beemployed as a reactant, said reactant being condensed with the toluidinemoiety. The ester group is subsequently hydrolyzed. In some instanceshydrolysis may occur during the reaction but the alcohol produced doesnot interfere with the desired reaction and is easily removed duringisolation and purification.

In addition to the use of the reactants employed in the above-describedreactions, other equivalently functioning reactants may be employed toproduce the desired novel compositions of this invention. For example,instead of employing a 2-halo-nicotinic acid (or ester thereof), anicotinic acid (or ester thereof) having an alkoxy, alkylthio,methylsulfonyl, nitro or other equivalently functioning substituent inthe 2-position thereof may be so employed. In such instances, the samereaction conditions used in the previous reactions would be employed.Alternatively, an N-substituted otoluidine reactant may be heated withthe foregoing 2- substituted nicotinic acids (or esters thereof) insteadof employing the previously described o-toluidine. Such equivalentlyfunctioning N-substituted o-toluidine reactants include thoseo-toluidines wherein a hydrogen atom attached to the nitrogen atom hasbeen replaced with substituents such as benzyl, lower alkyl or acyl.Again, in the use of these equivalently functioning reactants thepreviously described reaction conditions would be employed. In thoseinstances wherein the N-substituted o-toluidine reactant has beenemployed, the 2-(N-substituted-Z-methylanilino)- nicotinic acid (orester thereof) may be subjected to standard procedures to remove thebenzyl, lower alkyl and acyl radicals from the nitrogen atom. Thepreferred reaction may be summarized by the following schematicrepresentation:

wherein R is a member of the group consisting of hydrogen and loweralkyl; R is a member of the group consisting of alkoxy, alkythio,methylsulfonyl and nitro; and R" is a member of the group consisting oflower alkyl, benzyl and acyl.

Alternatively, the compounds embraced within the concepts of thisinvention may also be prepared from 2- amino nicotinic acid (or esterthereof) by means of a nucleophilic displacement reaction with ano-tylylhalide. The preparation of these compounds by this route isaffected in the same manner as in the previously described displacementreaction.

The foregoing reaction may be summarized by the following schematicrepresentation:

000R A COOR l l NH: CH N- N X a hydrolysis is chemically transformedinto the desired carboxyl radical.

The following examples are illustrative of the methods of synthesis ofthe tangible embodiments of this invention.

such metals which advantageously allow for greater EXAMPLE 1 Heat amixture of 44 g. of o-toluidine and 37 g. of 5 product. Recrystallizefrom acetonitrile giving 2-(2- methylanilino)-nicotinic acid, m.p.167168 C as a yellow solid.

EXAMPLE 2 2-(2-Methylanilino)-nicotinic Acid Heat a mixture of 9.4 g. of2-chloronicotinic acid and 12.9 g. of o-toluidine to 160 C in a metalbath. Covering the vessel, a vigorous reaction ensues with thetemperature of the reaction mixture rising to 230 C. The

reaction is completed in approximately 15 minutes and the completion isevidenced by a drop in the temperature of the reaction mixture. Extractand dilute the product of the reaction with dilute sodium hydroxidesolution and benzene. Separate the aqueous basic layer 3 5 andneutralize with dilute hydrochloric acid and filter to give2-(2-methylanilino)-nicotinic acid.

The tangible embodiments of this invention are acids, and are soluble inaqueous alkali. The alkali and the alkaline earth metal and amine saltsof the novel compound may be prepared by methods well known in the artfor the preparation of a salt of a strong base with a weak acid. Forexample, the alkali metal salt, preferably the sodium salt, may beobtained by evaporation of an alkaline solution (e.g. with sodiumhydroxide) of the anilino-nicotinic acid described herein.Alternatively, non-aqueous media may be employed. For example, by mixingan alcoholic solution of the anilinonicotinic acid together with analcoholic solution containing a stoichiometric quantity of an alkalimetal alkoxide and after evaporating the solvent, there is obtained thealkali metal salt which is soluble in water. In a similar fashion and byother known techniques other functional derivatives (i.e. otherpharmaceutically acceptable salts) are prepared. Representative of suchsalts are, in addition to sodium, those wherein the cation is ammonium,diethanol ammonium, potassium, lithium, calcium, aluminum and othertained by the condensation of an alkyl ester of the hereinabovedescribed anilinonicotinic acid with hydroxylamine hydrochloride in thepresence of sodiurn methoxide.

The tangible embodiments of the invention, in the form of the free acidor non-toxic pharmaceutically acceptable salt thereof, possess theinherent applied use characteristic of exerting an analgesic effect asdetermined by standard laboratory test procedures. Thus, the compoundsof this invention are useful in treating pain.

It is known that certain anilino nicotinic acids may produce analgesiabut there is associated with them a concomitant anti-inflammatoryactivity. Indeed, the anilino nicotinic acids under study today indicatethat they are primarily useful as anti-inflammatory agents and onlysecondarily, if at all, are they considered as analgesics. Quiteunexpectedly, it has been found that 2-(2-methylanilino)-nicotinic acidand the non-toxic pharmaceutically acceptable salts thereof exhibitsignificant analgesic activity without concomitant anti-inflammatory orulcerogenic effects. Thus, these compositions of matter are extremelyuseful in those conditions wherein only analgesic therapy is indicatedsuch as, for example, fractures, trauma, and toothache as well as theusual conditions for which analgesic therapy is indicated.

Based upon standard laboratory assay tests (e.g. the yeast paw test) ithas been determined that an analgesic effect suitable for thealleviation of pain is achieved when the compound of this invention isadministered to mammals in a dosage range of about 10 mg. per kg. toabout 40 mg. per kg. of body weight per day.

In their functions as therapeutically useful com pounds, it isadvantageous to administer the compounds to the host animal in admixturewith an acceptable pharmaceutical carrier suitable for enteral orparenteral administration, said carrier constituting a major portion ofthe admixture. Such preparations may be in such forms as, for example,tablets, capsules and suppositories, or in liquid forms, as for example,elixirs, emulsions, sprays and injectables. In the formulation ofpharmaceutical preparations there can be employed such substances whichdo not react with the active substance, as for example, water, gelatin,lactose, starches,

magnesium stearate, talc, vegetable oils, benzyl al- I cohols, gums,polyalkylene glycols, petroleum jelly and the like. The activeingredient of such pharmaceutical preparations is preferably present inthe preparations in such proportions by weight that the proportion byweight of the active ingredient to be administered lies between 0.1 and50 percent.

TABLET FORMULATION The following formulation provides for themanufacture of 1000 tablets:

Grams l 2-(2-methylanilino)-nicotinic acid 25.0 (2) Lactose, U.S.P.181.0 (3) Corn Starch, U.S.P. 92.5 (4) Magnesium Stearate l .5

Thoroughly granulate a mixture of 72.5 g. of corn starch and the lactosewith a paste prepared by dissolving 20 g. of corn starch in ml. of hotdistilled water. Dry the resulting granulation, add a blended mixture ofthe active ingredient (l) and the magnesium stearate. Thoroughly blendand then press into tablets of 300 mg. each.

CAPSULE FORMULATION The following formulation provides for themanufacture of 1000 capsules:

Grams 2-(2-methylanilino )-nicotinic acid 26") (2) Lactose 273.5 (3)Magnesium Stearate 1.5

PARENTERAL FORMULATION The following formulation provides for themanufacture of 1000 vials each containing mg. of active ingredient, asthe sodium salt.

2-(2-methylanilino )-nicotinic acid (sodium salt) Monobasic potassiumphosphate Water for injection U.S.P. g.s....ad 1.00 l.

Dissolve ingredients 1), (2) and (3) in approximately percent of thevolume of water and filter the resulting solution. Add to the filtratesufficient water to bring up to a 1000 ml. volume. Sterile-filter thesolution and aseptically fill one milliliter portions of the solutioninto 2 milliliter vials, then lyophilize. After the lyophilized cake isdry, aseptically stopper the vials with rubber plugs and seal.

I claim:

1. The process for alleviating pain which comprises administering to ananimal suffering from pain, a therapeutically efl'ective pain relievingquantity of 2- (2-methylanilino )-nicotinic acid or the non-toxicpharmaceutically acceptable salts thereof.

2. The process of claim 1 wherein said compound is 2-(2-methylanilino)-nicotinic acid.

3. The process of claim 1 wherein said compound is a non-toxicpharrnaceutically acceptable salt of 2-(2- methyl-ariilino )-nicotinicacid.

2. The process of claim 1 wherein said compound is2-(2-methylanilino)-nicotinic acid.
 3. The process of claim 1 whereinsaid compound is a non-toxic pharmaceutically acceptable salt of2-(2-methyl-anilino)-nicotinic acid.